Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia
Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd
Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd
View: Text | PDF
Research Article Oncology Therapeutics

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

Authors

Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd

×

Figure 3

The use of DHO plasma concentration to gauge HOSU-53 tolerability and toxicity.

Options: View larger image (or click on image) Download as PowerPoint
The use of DHO plasma concentration to gauge HOSU-53 tolerability and to...
(A) Multiple ascending dose study to determine the maximum in vivo daily tolerated oral dose of HOSU-53. Using the FLT3-mutant MOLM-13 CDX tumor–bearing model, 4 days after i.v. engraftment, NCG mice (n = 10/group) were enrolled to receive increasing HOSU-53 daily p.o. doses. aMice in the 30 mg/kg group showed weight loss by day 13 of treatment. Thus, a dosing holiday was instituted followed by resuming treatment on day 18 at 20 mg/kg reduced dosage. bMice in the 100 mg/kg groups showed weight loss instituting a dosing halt on day 6 of treatment. Acceptable tolerability was defined as a group mean body weight (BW) loss of less than 20% during the study. Any dosing regimen resulting in greater BW loss was considered above the maximum tolerated dose (MTD). Adjusted FDR P value *<0.05, ***≤0.0001. (B and C) Correlative efficacy and PK/PD in vivo analysis of HOSU-53. Using the FLT3-mutant MOLM-13 CDX tumor–bearing model, 4 days after i.v. engraftment, NCG mice (n = 10/group for survival study, n = 3/group for PK/PD analysis) were enrolled to receive increasing HOSU-53 oral doses to correlate efficacy (B) with the plasma concentration of HOSU-53 (PK) and on-target metabolite, DHO accumulation (PD) at day 1 and cumulative day 14 (C). Green dotted line represents the hypothesized threshold of tolerability. Data represent individual values of each mouse. Adjusted FDR P value ***≤0.0001. qd, daily; biwk, twice weekly.